ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
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DOI：
10.1038/sj.emboj.7600777
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发表时间：
2005-10-05
期刊：
影响因子：
11.4
通讯作者：
Koumenis, C
中科院分区：
文献类型：
--
作者：
Bi, MX;Naczki, C;Koumenis, C
肿瘤细胞对缺氧应激的适应是恶性进展的重要决定因素。虽然在这种情况下，HIF-1的作用得到了很多强调，但其他机制的作用尚未得到充分探讨。在这里，我们证明了在缺氧/缺氧条件下培养的细胞和在肿瘤缺氧区域转化的细胞激活了一个被称为综合应激反应（ISR）的翻译控制程序，该程序使细胞适应内质网（ER）应激。内质网激酶PERK和翻译起始因子eIF2 α突变或显性阴性PERK使ISR信号失活，会损害细胞在极端缺氧条件下的存活。与具有完整ISR的肿瘤相比，来自这些突变细胞系的肿瘤更小，在缺氧区域表现出更高水平的凋亡。此外，ISR靶点ATF4和CHOP的表达在人类肿瘤活检样本的缺氧区域被注意到。总的来说，这些发现表明，ISR的激活是肿瘤细胞适应缺氧所必需的，并表明这一途径是抗肿瘤方式的一个有吸引力的靶点。
Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we demonstrate that cells cultured under hypoxic/ anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum ( ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2 alpha or by a dominant-negative PERK impairs cell survival under extreme hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of the ISR targets ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities.